Liraglutide Attenuates Endothelial Dysfunction by Inhibiting Hyperglycemia-Induced Endothelial Cell Senescence Through the LARP7/SIRT1 Pathway.

Vascular endothelial cells (ECs) are pivotal in maintaining vascular homeostasis. Liraglutide (LIR) can prevent and reverse hyperglycemia-induced cell dysfunction. However, the mechanism by which it improves hyperglycemia-induced EC senescence remains unclear. This study investigates whether the La Ribonucleoprotein 7/Sirutin 1 (LARP7/SIRT1) signaling axis is essential for LIR efficacy in mitigating EC senescence and dysfunction. We treated senescent human umbilical vein ECs induced by high glucose levels with LIR and evaluated cell viability cell counting kit-8 (CCK-8 assay), senescence (SA-β-gal staining), and SASP alterations (qPCR). We also investigated the expression of senescence-related proteins and changes in the LARP7/SIRT1 signaling pathway using Western blot analysis. Additionally, reactive oxygen species levels were measured with 2',7'-Dichlorodihydrofluorescein diacetate (DCFH-DA), and changes in oxidative stress-related factors were assessed using specific assay kits. The effect of LIR on endothelial dysfunction was examined by cellular tube-forming assay and transwell assay after LARP7 knockdown/overexpression. LIR markedly improved cell vitality and the senescence phenotype while reducing oxidative stress. The LARP7/SIRT1 pathway emerged as crucial for its effectiveness. Following LARP7 knockdown, the therapeutic efficacy of LIR was notably attenuated. The overexpression of LARP7 enhanced the therapeutic efficacy of LIR. The tube formation and transwell assays further supported the hypothesis that LIR's beneficial impact on endothelial dysfunction depends on the LARP7/SIRT1 signaling axis. Our study reveals a novel aspect of LIR as an antidiabetic agent in delaying vascular aging driven by high glucose through targeting the LARP7/SIRT1 pathway. This discovery enhances the therapeutic value of LIR and proposes a new strategy for addressing vascular aging in treatments for elderly patients with diabetes.